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1.
Preprint | EuropePMC | ID: ppcovidwho-296845

ABSTRACT

To better understand the development of immunity against SARS-CoV-2 over time, we evaluated humoral and cellular responses a population-based cohort of SARS-CoV-2-infected individuals covering the full spectrum of COVID-19 up to 217 days after diagnosis. We characterized anti-Spike (S)-IgA and -IgG antibody responses in 431 individuals and found that about 85% develop and maintain anti-S-IgG responses over time. In a subsample of 64 participants selected for a detailed characterization of immune responses, we additionally evaluated anti-Nucleocapsid (N)-IgG antibodies and T cell responses specific to viral Membrane (M), N, and S proteins. Most participants had detectable T cell responses to at least one of the four peptide pools analyzed, which were more frequent than antibody seropositivity. We found a moderate correlation between antibody and T cell responses, which declined over time and suggests important variability in response patterns between individuals. The heterogeneity of immune trajectories was further analyzed using cluster analyses taking into account joint antibody and T cell responses over time. We identified five distinct immune trajectory patterns, which were characterized by specific antibody, T cell and T cell subset patterns along with disease severity and demographic factors. Higher age, male sex, higher disease severity and being a non-smoker was significantly associated with stronger immune responses. Overall, the results highlight that there is a consistent and maintained antibody response among most SARS-CoV-2-infected individuals, while T cell responses appear to be more heterogenous but potentially compensatory among those with low antibody responses.

2.
Cell Rep ; 37(2): 109814, 2021 10 12.
Article in English | MEDLINE | ID: covidwho-1433045

ABSTRACT

Control of the ongoing SARS-CoV-2 pandemic is endangered by the emergence of viral variants with increased transmission efficiency, resistance to marketed therapeutic antibodies, and reduced sensitivity to vaccine-induced immunity. Here, we screen B cells from COVID-19 donors and identify P5C3, a highly potent and broadly neutralizing monoclonal antibody with picomolar neutralizing activity against all SARS-CoV-2 variants of concern (VOCs) identified to date. Structural characterization of P5C3 Fab in complex with the spike demonstrates a neutralizing activity defined by a large buried surface area, highly overlapping with the receptor-binding domain (RBD) surface necessary for ACE2 interaction. We further demonstrate that P5C3 shows complete prophylactic protection in the SARS-CoV-2-infected hamster challenge model. These results indicate that P5C3 opens exciting perspectives either as a prophylactic agent in immunocompromised individuals with poor response to vaccination or as combination therapy in SARS-CoV-2-infected individuals.


Subject(s)
Broadly Neutralizing Antibodies/therapeutic use , COVID-19/drug therapy , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , B-Lymphocytes/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/immunology , Cell Line , Cricetinae , Disease Models, Animal , Epitopes/immunology , Humans , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Fab Fragments/metabolism , Neutralization Tests , Protein Binding/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/ultrastructure , Structure-Activity Relationship , Vaccination
3.
Nat Commun ; 12(1): 5215, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1392854

ABSTRACT

Achieving sufficient worldwide vaccination coverage against SARS-CoV-2 will require additional approaches to currently approved viral vector and mRNA vaccines. Subunit vaccines may have distinct advantages when immunizing vulnerable individuals, children and pregnant women. Here, we present a new generation of subunit vaccines targeting viral antigens to CD40-expressing antigen-presenting cells. We demonstrate that targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to CD40 (αCD40.RBD) induces significant levels of specific T and B cells, with long-term memory phenotypes, in a humanized mouse model. Additionally, we demonstrate that a single dose of the αCD40.RBD vaccine, injected without adjuvant, is sufficient to boost a rapid increase in neutralizing antibodies in convalescent non-human primates (NHPs) exposed six months previously to SARS-CoV-2. Vaccine-elicited antibodies cross-neutralize different SARS-CoV-2 variants, including D614G, B1.1.7 and to a lesser extent B1.351. Such vaccination significantly improves protection against a new high-dose virulent challenge versus that in non-vaccinated convalescent animals.


Subject(s)
CD40 Antigens/immunology , COVID-19 Vaccines/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Antigen-Presenting Cells/immunology , B-Lymphocytes/immunology , Convalescence , Humans , Macaca , Mice , Mutation , Protein Domains , Reinfection/prevention & control , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , T-Lymphocytes/immunology , Vaccination , Vaccines, Subunit/immunology
4.
Nat Commun ; 12(1): 4888, 2021 08 09.
Article in English | MEDLINE | ID: covidwho-1349667

ABSTRACT

The objective of the present study was to identify biological signatures of severe coronavirus disease 2019 (COVID-19) predictive of admission in the intensive care unit (ICU). Over 170 immunological markers were investigated in a 'discovery' cohort (n = 98 patients) of the Lausanne University Hospital (LUH-1). Here we report that 13 out of 49 cytokines were significantly associated with ICU admission in the three cohorts (P < 0.05 to P < 0.001), while cellular immunological markers lacked power in discriminating between ICU and non-ICU patients. The cytokine results were confirmed in two 'validation' cohorts, i.e. the French COVID-19 Study (FCS; n = 62) and a second LUH-2 cohort (n = 47). The combination of hepatocyte growth factor (HGF) and C-X-C motif chemokine ligand 13 (CXCL13) was the best predictor of ICU admission (positive and negative predictive values ranging from 81.8% to 93.1% and 85.2% to 94.4% in the 3 cohorts) and occurrence of death during patient follow-up (8.8 fold higher likelihood of death when both cytokines were increased). Of note, HGF is a pleiotropic cytokine with anti-inflammatory properties playing a fundamental role in lung tissue repair, and CXCL13, a pro-inflammatory chemokine associated with pulmonary fibrosis and regulating the maturation of B cell response. Up-regulation of HGF reflects the most powerful counter-regulatory mechanism of the host immune response to antagonize the pro-inflammatory cytokines including CXCL13 and to prevent lung fibrosis in COVID-19 patients.


Subject(s)
COVID-19/immunology , COVID-19/mortality , Chemokine CXCL13/immunology , Cytokines/immunology , Hepatocyte Growth Factor/immunology , Biomarkers/blood , CD4-Positive T-Lymphocytes , COVID-19/blood , COVID-19/diagnosis , Chemokine CXCL13/genetics , Cytokines/blood , Hepatocyte Growth Factor/genetics , Hospitalization , Humans , Intensive Care Units , Pulmonary Fibrosis , SARS-CoV-2/isolation & purification , Severity of Illness Index
5.
Open Forum Infect Dis ; 8(7): ofab149, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1324645

ABSTRACT

Background: Research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission within households and other close settings using serological testing is scarce. Methods: We invited coronavirus disease 2019 (COVID-19) cases diagnosed between February 27 and April 1, 2020, in Canton of Vaud, Switzerland, to participate, along with household members and other close contacts. Anti-SARS-CoV-2 immunoglobulin G antibodies were measured using a Luminex immunoassay. We estimated factors associated with serological status using generalized estimating equations. Results: Overall, 219 cases, 302 household members, and 69 other close contacts participated between May 4 and June 27, 2020. More than half of household members (57.2%; 95% CI, 49.7%-64.3%) had developed a serologic response to SARS-CoV-2, while 19.0% (95% CI, 10.0%-33.2%) of other close contacts were seropositive. After adjusting for individual and household characteristics, infection risk was higher in household members aged ≥65 years than in younger adults (adjusted odds ratio [aOR], 3.63; 95% CI, 1.05-12.60) and in those not strictly adhering to simple hygiene rules like hand washing (aOR, 1.80; 95% CI, 1.02-3.17). The risk was lower when more than 5 people outside home were met during semiconfinement, compared with none (aOR, 0.35; 95% CI, 0.16-0.74). Individual risk of household members to be seropositive was lower in large households (22% less per each additional person). Conclusions: During semiconfinement, household members of a COVID-19 case were at very high risk of getting infected, 3 times more than close contacts outside home. This highlights the need to provide clear messages on protective measures applicable at home. For elderly couples, who were especially at risk, providing external support for daily basic activities is essential.

6.
Sci Transl Med ; 13(605)2021 08 04.
Article in English | MEDLINE | ID: covidwho-1309799

ABSTRACT

The detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies in the serum of an individual indicates previous infection or vaccination. However, it provides limited insight into the protective nature of this immune response. Neutralizing antibodies recognizing the viral spike protein are more revealing, yet their measurement traditionally requires virus- and cell-based systems that are costly, time-consuming, inflexible, and potentially biohazardous. Here, we present a cell-free quantitative neutralization assay based on the competitive inhibition of trimeric SARS-CoV-2 spike protein binding to the angiotensin-converting enzyme 2 (ACE2) receptor. This high-throughput method matches the performance of the gold standard live virus infection assay, as verified with a panel of 206 seropositive donors with varying degrees of infection severity and virus-specific immunoglobulin G titers, achieving 96.7% sensitivity and 100% specificity. Furthermore, it allows for the parallel assessment of neutralizing activities against multiple SARS-CoV-2 spike protein variants of concern. We used our assay to profile serum samples from 59 patients hospitalized with coronavirus disease 2019 (COVID-19). We found that although most sera had high activity against the 2019-nCoV parental spike protein and, to a lesser extent, the α (B.1.1.7) variant, only 58% of serum samples could efficiently neutralize a spike protein derivative containing mutations present in the ß (B.1.351) variant. Thus, we have developed an assay that can evaluate effective neutralizing antibody responses to SARS-CoV-2 spike protein variants of concern after natural infection and that can be applied to characterize vaccine-induced antibody responses or to assess the potency of monoclonal antibodies.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/therapy , Humans , Immunization, Passive , Neutralization Tests , Spike Glycoprotein, Coronavirus
7.
Lancet Rheumatol ; 3(9): e617, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1301108
8.
BMJ Open ; 11(7): e049232, 2021 07 05.
Article in English | MEDLINE | ID: covidwho-1297975

ABSTRACT

OBJECTIVE: To assess the SARS-CoV-2 transmission in healthcare workers (HCWs) using seroprevalence as a surrogate marker of infection in our tertiary care centre according to exposure. DESIGN: Seroprevalence cross-sectional study. SETTING: Single centre at the end of the first COVID-19 wave in Lausanne, Switzerland. PARTICIPANTS: 1874 of 4074 responders randomly selected (46% response rate), stratified by work category among the 13 474 (13.9%) HCWs. MAIN OUTCOME MEASURES: Evaluation of SARS-CoV-2 serostatus paired with a questionnaire of SARS-CoV-2 acquisition risk factors internal and external to the workplace. RESULTS: The overall SARS-CoV-2 seroprevalence rate among HCWs was 10.0% (95% CI 8.7% to 11.5%). HCWs with daily patient contact did not experience increased rates of seropositivity relative to those without (10.3% vs 9.6%, respectively, p=0.64). HCWs with direct contact with patients with COVID-19 or working in COVID-19 units did not experience increased seropositivity rates relative to their counterparts (10.4% vs 9.8%, p=0.69 and 10.6% vs 9.9%, p=0.69, respectively). However, specific locations of contact with patients irrespective of COVID-19 status-in patient rooms or reception areas-did correlate with increased rates of seropositivity (11.9% vs 7.5%, p=0.019 and 14.3% vs 9.2%, p=0.025, respectively). In contrast, HCWs with a suspected or proven SARS-CoV-2-infected household contact had significantly higher seropositivity rates than those without such contacts (19.0% vs 8.7%, p<0.001 and 42.1% vs 9.4%, p<0.001, respectively). Finally, consistent use of a mask on public transportation correlated with decreased seroprevalence (5.3% for mask users vs 11.2% for intermittent or no mask use, p=0.030). CONCLUSIONS: The overall seroprevalence was 10% without significant differences in seroprevalence between HCWs exposed to patients with COVID-19 and HCWs not exposed. This suggests that, once fully in place, protective measures limited SARS-CoV-2 occupational acquisition within the hospital environment. SARS-CoV-2 seroconversion among HCWs was associated primarily with community risk factors, particularly household transmission.


Subject(s)
COVID-19 , SARS-CoV-2 , Cross-Sectional Studies , Health Personnel , Humans , Seroepidemiologic Studies , Switzerland/epidemiology , Tertiary Care Centers
9.
iScience ; 24(7): 102711, 2021 Jul 23.
Article in English | MEDLINE | ID: covidwho-1281437

ABSTRACT

The identification of patients with coronavirus disease 2019 and high risk of severe disease is a challenge in routine care. We performed cell phenotypic, serum, and RNA sequencing gene expression analyses in severe hospitalized patients (n = 61). Relative to healthy donors, results showed abnormalities of 27 cell populations and an elevation of 42 cytokines, neutrophil chemo-attractants, and inflammatory components in patients. Supervised and unsupervised analyses revealed a high abundance of CD177, a specific neutrophil activation marker, contributing to the clustering of severe patients. Gene abundance correlated with high serum levels of CD177 in severe patients. Higher levels were confirmed in a second cohort and in intensive care unit (ICU) than non-ICU patients (P < 0.001). Longitudinal measurements discriminated between patients with the worst prognosis, leading to death, and those who recovered (P = 0.01). These results highlight neutrophil activation as a hallmark of severe disease and CD177 assessment as a reliable prognostic marker for routine care.

10.
Neurol Neuroimmunol Neuroinflamm ; 8(5)2021 07.
Article in English | MEDLINE | ID: covidwho-1278138

ABSTRACT

OBJECTIVE: Coronavirus disease (COVID-19) has been associated with a large variety of neurologic disorders. However, the mechanisms underlying these neurologic complications remain elusive. In this study, we aimed at determining whether neurologic symptoms were caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) direct infection or by either systemic or local proinflammatory mediators. METHODS: In this cross-sectional study, we checked for SARS-CoV-2 RNA by quantitative reverse transcription PCR, SARS-CoV-2-specific antibodies, and 49 cytokines/chemokines/growth factors (by Luminex) in the CSF +/- sera of a cohort of 22 COVID-19 patients with neurologic presentation and 55 neurologic control patients (inflammatory neurologic disorder [IND], noninflammatory neurologic disorder, and MS). RESULTS: We detected anti-SARS-CoV-2 immunoglobulin G in patients with severe COVID-19 with signs of intrathecal synthesis for some of them. Of the 4 categories of tested patients, the CSF of IND exhibited the highest level of cytokines, chemokines, and growth factors. By contrast, patients with COVID-19 did not present overall upregulation of inflammatory mediators in the CSF. However, patients with severe COVID-19 (intensive care unit patients) exhibited higher concentrations of CCL2, CXCL8, and vascular endothelium growth factor A (VEGF-A) in the CSF than patients with a milder form of COVID-19. In addition, we could show that intrathecal CXCL8 synthesis was linked to an elevated albumin ratio and correlated with the increase of peripheral inflammation (serum hepatocyte growth factor [HGF] and CXCL10). CONCLUSIONS: Our results do not indicate active replication of SARS-CoV-2 in the CSF or signs of massive inflammation in the CSF compartment but highlight a specific impairment of the neurovascular unit linked to intrathecal production of CXCL8.


Subject(s)
Brain Diseases/etiology , COVID-19/complications , Cytokines/cerebrospinal fluid , Inflammation/etiology , Neurovascular Coupling , SARS-CoV-2/pathogenicity , Adult , Aged , Aged, 80 and over , Antibodies, Viral/cerebrospinal fluid , Brain Diseases/cerebrospinal fluid , Brain Diseases/immunology , Brain Diseases/physiopathology , COVID-19/cerebrospinal fluid , COVID-19/immunology , Critical Care , Cross-Sectional Studies , Cytokines/blood , Electroencephalography , Female , Humans , Immunoglobulin G/cerebrospinal fluid , Inflammation/cerebrospinal fluid , Inflammation/immunology , Interleukin-8/cerebrospinal fluid , Male , Middle Aged , Neurovascular Coupling/immunology , SARS-CoV-2/immunology , Severity of Illness Index , Young Adult
11.
Microorganisms ; 9(4)2021 Apr 10.
Article in English | MEDLINE | ID: covidwho-1178361

ABSTRACT

Following the Swiss Federal Office of Public Health (FOPH) authorization of the rapid antigen test (RAT), we implemented the use of the RAT in the emergency ward of our university hospital for patients' cohorting. RAT triaging in association with RT-PCR allowed us to promptly isolate positive patients and save resources. Among 532 patients, overall sensitivities were 48.3% for Exdia and 41.2% for Standard Q®, PanbioTM and BD Veritor™. All RATs exhibited specificity above 99%. Sensitivity increased to 74.6%, 66.2%, 66.2% and 64.8% for Exdia, Standard Q®, PanbioTM and BD Veritor™, respectively, for viral loads above 105 copies/mL, to 100%, 97.8%, 96.6% and 95.6% for viral loads above 106 copies/mL and 100% for viral loads above 107 copies/mL. Sensitivity was significantly higher for patients with symptoms onset within four days (74.3%, 69.2%, 69.2% and 64%, respectively) versus patients with the evolution of symptoms longer than four days (36.8%, 21.1%, 21.1% and 23.7%, respectively). Among COVID-19 asymptomatic patients, sensitivity was 33%. All Immunoglobulin-A-positive patients resulted negative for RAT. The RAT might represent a useful resource in selected clinical settings as a complementary tool in RT-PCR for rapid patient triaging, but the lower sensitivity, especially in late presenters and COVID-19 asymptomatic subjects, must be taken into account.

12.
J Virol ; 95(3)2021 01 13.
Article in English | MEDLINE | ID: covidwho-1028544

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses to the spike (S) protein monomer, S protein native trimeric form, or the nucleocapsid (N) proteins were evaluated in cohorts of individuals with acute infection (n = 93) and in individuals enrolled in a postinfection seroprevalence population study (n = 578) in Switzerland. Commercial assays specific for the S1 monomer, for the N protein, or within a newly developed Luminex assay using the S protein trimer were found to be equally sensitive in antibody detection in the acute-infection-phase samples. Interestingly, compared to anti-S antibody responses, those against the N protein appear to wane in the postinfection cohort. Seroprevalence in a "positive patient contacts" group (n = 177) was underestimated by N protein assays by 10.9 to 32.2%, while the "randomly selected" general population group (n = 311) was reduced by up to 45% relative to the S protein assays. The overall reduction in seroprevalence targeting only anti-N antibodies for the total cohort ranged from 9.4 to 31%. Of note, the use of the S protein in its native trimer form was significantly more sensitive compared to monomeric S proteins. These results indicate that the assessment of anti-S IgG antibody responses against the native trimeric S protein should be implemented to estimate SARS-CoV-2 infections in population-based seroprevalence studies.IMPORTANCE In the present study, we have determined SARS-CoV-2-specific antibody responses in sera of acute and postinfection phase subjects. Our results indicate that antibody responses against viral S and N proteins were equally sensitive in the acute phase of infection, but that responses against N appear to wane in the postinfection phase where those against the S protein persist over time. The most sensitive serological assay in both acute and postinfection phases used the native S protein trimer as the binding antigen, which has significantly greater conformational epitopes for antibody binding compared to the S1 monomer protein used in other assays. We believe these results are extremely important in order to generate correct estimates of SARS-CoV-2 infections in the general population. Furthermore, the assessment of antibody responses against the trimeric S protein will be critical to evaluate the durability of the antibody response and for the characterization of a vaccine-induced antibody response.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Coronavirus Nucleocapsid Proteins/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , COVID-19/blood , COVID-19/epidemiology , Female , Humans , Immunoassay , Immunoglobulin A/blood , Immunoglobulin G/blood , Male , Phosphoproteins/immunology , Protein Multimerization , Sensitivity and Specificity , Seroepidemiologic Studies , Spike Glycoprotein, Coronavirus/chemistry , Switzerland/epidemiology , Time Factors
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